open zika presentation
TRANSCRIPT
Prof. Carolina Horta Andrade, Ph.D.
[email protected]://openzika.ufg.br
Alexander Perryman, [email protected]
Sean Ekins, [email protected]
How it started
• SE discussion with Antony Williams and others
• Blogged about Zika in Jan• Took hashtag #ZikaOpen in Jan• ‘Asked’ for tropical disease
voucher for Zika• Initially was not sure what could
be done – Jan 26th Email discussion with Priscilla L. Yang suggested glycoprotein E– Jan 27th
• Analysis of sequence• Swiss Model
Communication• Reached out on Twitter and blog to
enlist ideas and help• Emailed program officers at NIH
NIAID• Also proposed that open
repositories be created and journals waive charges for papers
• Several scientists responded• Connected to collaborators • Started writing up a white paper• Used GoogleDocs to collaborate
http://www.viprbrc.org/brc/home.spg?decorator=flavi_zika
By Jan ‘16 -Zika is here but we are not ready for it
• Common responses:• Concern for effects of drug on pregnant women• Zika virus is mild• Will wait for a vaccine
• But:• It is sexually transmitted• There are severe neurological issues for some• We are still waiting for vaccines for HIV, malaria, TB etc
Little visibility for antiviral efforts against Zika
CDC report: http://www.cdc.gov/zika/geo/active-countries.html
Zika Global Crisis
Confirmed in + of 50 countries
WHO said that ZIKV may spread in Europe this summer.
Microcephaly and other neurological issues
Zika virus (ZIKV) - reported in 1947
Neglected until 2015
May, 2015 - outbreak in Brazil that quickly has spread to the Americas
Zika virus (ZIKV)
http://viralzone.expasy.org/all_by_species/6756.html
Virion
Enveloped, spherical, about 50 nm in diameter. The surface proteins are arranged in an icosahedral-like symmetry.
Genome
Proposed workflow for rapid drug discovery against Zika virus
Ekins, S. et al., Open Drug Discovery for the Zika Virus. F1000Research 2016, 5, 1–12 (doi: 10.12688/f1000research.8013.1)
SBDD or LBDD??
Compounds and chemical libraries suggested for testing against ZIKV
Ekins, S. et al., Open Drug Discovery for the Zika Virus. F1000Research 2016, 5, 1–12 (doi: 10.12688/f1000research.8013.1)
Art of THE CELL
• After first paper was published…• Contacted by John Liebler• He wanted to illustrate the virus!• This got me thinking about the
complete virus• Needed to read up on flavivirus
mechanism• After a few days realized he
needed a different conformation of glycoprotein E
• Klein et al.,
Illustration for Dengue virus
Klein et al., J Virol. 2013 Feb;87(4):2287-93.
GLYCOPROTEIN E FUNCTION
Other proteins IN ZIKA
GLYCOPROTEIN E DIMER conformation HOMOLOGY MODEL
JOHN’S BLOG
Images by John Liebler
Spot the Difference – and we did this over a month before cryo-EM structures were
publishedJohn produced images of both Zika and Dengue
Zika appears ‘Pimplier’Dimer has narrow letter box grooveDengue has a bigger pore between intersection of 5 dimersDoes this help us understand how drugs could access virus?Does it help understand function?Opportunities for vaccine design?
Images by John Liebler
Comparing Flavivirus cryo-EM’s
Then why not model every protein • Used Swissmodel• Took a few hours over weekend.
ZIKV strain (GenBank)
SWISS-MODEL server
Selection: Global Model Quality Estimation (GMQE) and QMEAN statistical parameters
Stereochemical quality -> PROCHECK
NS5 (A), FtsJ (B), HELICc (C), DEXDc (D), Peptidase S7 (E), NS1 (F), E Stem (G), Glycoprotein M (H), Propeptide (I), Capsid (J), and Glycoprotein E (K)
Ekins, S.; et al., Illustrating and Homology Modeling the Proteins of the Zika Virus. F1000Research 2016, 5, 275.
Homology Modeling
Stereochemical quality: PROCHECK
15 proteins -> 11 proteins
NS5 (A), FtsJ (B), HELICc (C), DEXDc (D), Peptidase S7 (E), NS1 (F), E Stem (G), Glycoprotein M (H), Propeptide (I), Capsid (J), and Glycoprotein E (K)
Homology Modeling
Ekins, S.; et al., Illustrating and Homology Modeling the Proteins of the Zika Virus. F1000Research 2016, 5, 275.
How it OpenZika started
Dr. Sean Ekins Dr. Alex Perryman
IBM philanthropic initiative, launched in 2004, that provides massive supercomputing power for scientists, without any costs, by using the idle processing power of computer or Android devices of volunteers.
It is a global research collaboration project
Our main goal is to accelerate the discovery of an effective treatment for Zika virus
Virtual screening of millions of compounds
20 millions compounds90 millions compounds
How WCG will contribute to this research?
MAIN GOALInnovative project to discover a new anti-viral drug to treat patients
infected with the Zika virusGenes or targets involved in a diseaseChemical space (library)
Drug candidates for Zika virus
Envelope Glycoprotein (PDB ID: 5JHM)
NS1 protein (PDB ID: 5IY3, 5K6K)
NS3 helicase (PDB ID:5JMT, 5JRZ)
NS2B/NS3 protease (PDB ID: 5LC0)
ZIKV protein Crystallographic structures
NS1 (5iy3) and HM protein
RMSD: 0.896 Å
NS1 (5k6k) and HM proteinRMSD: 0.812 Å
Glycoprotein E (5jhm) and HM proteinRMSD: 1.860 Å
NS2B/NS3 (5jrz) and HM protein (peptidase S7)
RMSD: 0.824 Å
Comparison Homology Modeling X Crystal Structures
NS3 helicase5jmt and HM (HELICc) proteinRMSD: 0.732 Å
NS3 helicase (FP strain)5jrz and HM (HELICc) proteinRMSD: 0.746 Å
NS3 helicase5jmt and HM (DEXDc) proteinRMSD: 0.894 Å
NS3 helicase (FP strain)5jrz and HM (DEXDc) proteinRMSD: 0.830 Å
Comparison Homology Modeling X Crystal Structures
OpenZika = # crunching for a cure
Building on GO FAM experience, to develop & hone new workflows creating a new platform for time & cost efficient responses to emerging infectious diseases
Screening millions of compounds vs. Zika, Dengue, West Nile, Yellow Fever, JEV, HCV (with some targets from Mtb, Klebsiella pneum., Pseudomonas aeur., and Bacillus anthracis)
Ekins, S., Perryman, A.L., & Andrade, C. PLoS NTD (Oct. 20, 2016)
Positive Controls:
NS5 class: 2 binding sites
Site 1: related to the ligand 2′-deoxy-2′-fluoro-2′-methyluridine 5′-(trihydrogen diphosphate) position
Site 2: related to the ligand S-Adenosyl Methionine (SAM) position
DOCKING
Crystal binding mode 2: purplePredicted binding mode 2: cyan
Crystal binding mode 1: purplePredicted binding mode 1: greenAutoDock Vina
Identified 15 candidates for assays (from library of 7,628 approved drugs & clinical candidates)
These are predicted to bind the (apo) ZIKV NS3 helicase (3 of the 15 are shown above)
After medicinal chemistry inspection, we selected 8 to order & assay (but 1 is too expensive, and 1 is restricted by the DEA)
5 of the 6 we ordered passed LC/MS quality control & will be assayed at UCSD
1st candidates from OZhave been identified
NS3 helicase (PDB ID 5jmt)
Timeline
Mid-May – Oct. 6, 2016: 60,000 volunteers donated CPU time from ~ 240,000 devices >11,000 CPU years have been donated to OpenZika
1.242 billion different docking jobs have been submitted 207 binding sites on 138 different protein targets are involved
2-5 different binding sites are targeted / protein 6 million compounds are docked against each site
11 million out of a new library of 38 million compounds have been prepared for future docking experiments
739 million docking results have been sent back to our server
Currently visually inspecting the docking results against the NS3 helicase:RNA complex 13 new candidates identified
press
• This work has not been funded• Please contact any of us to contribute time, effort,
molecules• [email protected]• Twitter: @collabchem
#ZikaOpen
WHAT IF WEVolunteered our computers and phones to..
1.24 billion docking jobs submitted
11,734 CPU years of crunching time
And it cost $0Source: WCG
We've docked ~ 6 million compounds
OPENZIKAhttps://www.worldcommunitygrid.org/
Our Team
Be a WCG volunteer and help our research!!! We need you!http://openzika.ufg.br
Carolina Andrade Sean EkinsAlex Perryman
Rodolpho Braga Melina Mottin Roosevelt Silva Wim Degrave Ana Carolina Ramos João Herminio
Lucio Freitas Jr.Jair Lage Joel Freundlich
And more….
Tom Stratton
Priscilla L. Yang